Syntheses of biotin are described in U.S. Pat. No. 2,489,232 and in Lavielle et al, "A Total Synthesis of Biotin . . . ", Journal of the American Chemical Society, volume 100, pages 1558-1563 (1978). Several of these syntheses include the step of reacting potassium salt of meso-2,3-bis(benzylamino)succinic acid [the CAS Registry No. of meso-2,3-bis(benzylamino)succinic acid is 55645-40-4] with phosgene and potassium hydroxide in the presence of water and either xylene or toluene. Although the patent and the Lavielle et al paper in their general descriptions refer to reacting the meso-2,3-bis(benzylamino)succinic acid with phosgene and potassium hydroxide, it is clear from the experimental sections that at the high values of pH involved, it is potassium salt of meso-2,3-bis(benzylamino)succinic acid which is reacted with the phosgene and potassium hydroxide. Upon completion of the reaction, the entire reaction mixture is acidified to precipitate 2-oxo-1,3-dibenzyl-4,5-cis-imidazolidinedicarboxylic acid [CAS Registry No. 51591-75-4] (hereinafter referred to for brevity as "cyclo acid" ) and meso-2,3-bis(benzylamino)succinic acid, the potassium salt of which remained unreacted during the phosgenation reaction. For brevity and in keeping with ordinary chemical usage, such acid is hereinafter referred to as "unreacted meso-2,3-bis(benzylamino)succinic acid." The precipitate is then further processed to separate the unreacted meso-2,3-bis(benzylamino)succinic acid from the desired cyclo acid. The yield of cyclo acid based on the meso-2,3-bis(benzylamino)succinic acid equivalent of its potassium salt in such processes is low as is evidenced by the large amounts of unreacted meso-2,3-bis(benzylamino)succinic acid recovered. For example, the recovered unreacted meso-2,3-bis(benzylamino)succinic acid reported in column 4 of U.S. Pat. No. 2,489,232 amounted to almost 34 percent of the meso-2,3-bis(benzylamino)succinic acid charged. Similarly, the recovered unreacted meso-2,3-bis(benzylamino)succinic acid is reported in the Lavielle et al paper, cited above, as being 20 percent; however calculation shows it to be nearly 23 percent.
More recently it was found that cyclo acid could be produced in higher yields and with less contamination by unreacted meso-2,3-bis(benzylamino)succinic acid by using methylene chloride as the substantially water-immiscible inert organic solvent in the process rather than toluene or xylene. Further improvement was obtained by separating the liquid organic phase and the aqueous phase after phosgenation but before acidification of the aqueous phase.
Although methylene chloride is a satisfactory substantially water-immiscible inert organic solvent from the technical viewpoint, it has come under increasing attack as a volatile environmental pollutant. Since solvents often perform differently in the process and since there are few, if any, general principles which would allow one to predict in advance the utility of one solvent over another, the search is largely empirical in nature.